CN1863524A - Neutralizing agent for cavitating toxin - Google Patents
Neutralizing agent for cavitating toxin Download PDFInfo
- Publication number
- CN1863524A CN1863524A CNA2004800288070A CN200480028807A CN1863524A CN 1863524 A CN1863524 A CN 1863524A CN A2004800288070 A CNA2004800288070 A CN A2004800288070A CN 200480028807 A CN200480028807 A CN 200480028807A CN 1863524 A CN1863524 A CN 1863524A
- Authority
- CN
- China
- Prior art keywords
- vaca
- lupuli
- flos
- nertralizer
- effective ingredient
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000000314 lubricant Substances 0.000 description 1
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- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
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- 229960002216 methylparaben Drugs 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 235000014593 oils and fats Nutrition 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 239000013588 oral product Substances 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
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- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- SUWYPNNPLSRNPS-UNTSEYQFSA-N plaunotol Chemical compound CC(C)=CCC\C(C)=C\CC\C(CO)=C\CC\C(C)=C\CO SUWYPNNPLSRNPS-UNTSEYQFSA-N 0.000 description 1
- SUWYPNNPLSRNPS-UHFFFAOYSA-N plaunotol Natural products CC(C)=CCCC(C)=CCCC(CO)=CCCC(C)=CCO SUWYPNNPLSRNPS-UHFFFAOYSA-N 0.000 description 1
- 229950009291 plaunotol Drugs 0.000 description 1
- 229920002492 poly(sulfone) Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920006393 polyether sulfone Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 229920002414 procyanidin Polymers 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- GFWRVVCDTLRWPK-KPKJPENVSA-N sofalcone Chemical compound C1=CC(OCC=C(C)C)=CC=C1\C=C\C(=O)C1=CC=C(OCC=C(C)C)C=C1OCC(O)=O GFWRVVCDTLRWPK-KPKJPENVSA-N 0.000 description 1
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- 239000004094 surface-active agent Substances 0.000 description 1
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- 239000003826 tablet Substances 0.000 description 1
- 229960005053 tinidazole Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
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- 230000002477 vacuolizing effect Effects 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
- C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
It is intended to provide a drug, a quasi drug, a food or a drink having an effect of preventing, preventing recurrence or treating digestive diseases, in which Helicobacter pylori participates, as well as an effect of killing Helicobacter pylori while showing little side effects and being free from any risk of the occurrence of a tolerant strain. Namely, a drug, a quasi drug, a food or a drink containing, as the active ingredient, proanthocyanidines having an effect of neutralizing (attenuating) a cavitating toxin produced by Helicobacter pylori, particulaly preferably proanthocyanigines originating in immature apple fruit or hop bract.
Description
Technical field
The present invention relates to prevention, anti-recurrence or treatment and helicobacter pylori (Helicobacter pylori) relevant chylopoietic disease and the nertralizer of the VacA that helicobacter pylori produced, medicine, medicine part outer article and diet product, they contain and have the VacA that helicobacter pylori is produced and do not have the procyanidin class of the effect that poisons, be preferably the procyanidin class that obtains as effective ingredient from Fructus Mali pumilae or Flos lupuli (Flos Humuli Lupuli) especially.
Background technology
Flos lupuli (Flos Humuli Lupuli) (Humulus lupuls) is the Cannabaceae perennial plant, and its globe daisy (sophisticated unfertilized female flower) is commonly referred to as Flos lupuli (Flos Humuli Lupuli).Except this flower portion, also there are various pieces such as leaf, climing, root in the Flos lupuli (Flos Humuli Lupuli).The lupulin that exists in the globe daisy of Flos lupuli (Flos Humuli Lupuli) part (yellow particle that forms at the interior luxuriant root of cone) is the source of the bitterness and the fragrance of Flos lupuli (Flos Humuli Lupuli), is important beer raw material with yeast, Fructus Hordei Germinatus in brewing.In addition, in folkd therapy Flos lupuli (Flos Humuli Lupuli) as tranquilizer and anti-estrualization agent and general.The Flos lupuli (Flos Humuli Lupuli) bract has been removed the lupulin part and has been obtained from the Flos lupuli (Flos Humuli Lupuli) globe daisy, be useless in brewing, is removed when beer brewing under the different situations, generates as by-product.At this moment, the Flos lupuli (Flos Humuli Lupuli) bract does not have other especially effectively to utilize method except the fertilizer of using as soil improvement, therefore wishes to develop the method for utilizing of high additive value more.
In the applicant's the application in the related patent documentation 1,2,3,4,5,6, confirmed that Flos lupuli (Flos Humuli Lupuli), the Polyphenols that particularly comes from the Flos lupuli (Flos Humuli Lupuli) bract have effect, topoisomerase enzyme inhibition that antioxidation, the bubble static stabilization to the foaming Fructus Hordei Germinatus beverage, dental caries effect, deodorization, anticancer shift.In addition, in patent documentation 7, confirmed to have neutralization to having the active archon of RNAN-glycosidase activity or ADP ribosyltransferase.
But, up to the present,, also do not have the example of clear and definite its neutralization (nothing poisons) effect to the VacA that helicobacter pylori produced for the procyanidin class that comes from Flos lupuli (Flos Humuli Lupuli).
The gram negative bacilli of helicobacter pylori (following only be called " pyloric bacteria ") for having the helical form form, since it existed since Warren and Marshal report (non-patent literature 1), chylopoietic diseases' such as clear and definite itself and acute gastritis, chronic gastritis, gastric ulcer, duodenal ulcer morbidity had much relations (with reference to non-patent literature 2,3,4).In addition since 90% or above patients with gastric cancer be the bacillicarrier etc. of pyloric bacteria, so the pyloric bacteria probability relevant with the generation of gastric cancer is higher, WHO has delivered " pyloric bacteria is the cancerigenic factor of gastric cancer really " in 1994.
As the cause of disease factor that produces pyloric bacteria, urease, catalase, lipopolysaccharide (LPS) etc. have been reported so far, but it is clear and definite in recent years, give the VacA (VacA) that causes vacuolar degeneration by throwing separately to the mucomembranous cell of stomach, can in animal model, cause gastritis (non-patent literature 5), thereby recognize that rapidly VacA is that the main diseases of pyloric bacteria is because of the factor.
All the time, in the treatment of ulcer diseases such as gastric ulcer, duodenal ulcer, antiulcer agents such as sofalcone, plaunotol have been used; Proton pump inhibitor such as omeprazole, lansoprazole (PPI); Gastric acid secretion inhibitor such as famotidine, cimetidine (H2 blocker) etc.But these medicines do not have the proliferation inhibiting effect to pyloric bacteria, are the symptomatic therapy medicaments to ulcer disease.Therefore, though can see by of the healing of above-mentioned medicament ulcer disease because pyloric bacteria remains in the stomach, therefore have treatment after finishing 1 year with interior relapse rate up to 80~90% shortcoming.
In order to overcome above-mentioned shortcoming, except symptomatic therapy, also proposed to remove the Therapeutic Method of pyloric bacteria, the antibiotic such as amoxicillin, clarithromycin, metronidazole, tinidazole that pyloric bacteria had antibacterial effect are used clinically to some extent.Now, with proton pump inhibitor and the combination of antibiotic 2 kinds of medicaments, be novel 3 doses and become the main flow of degerming treatment with therapy.
But at novel 3 doses and with in the therapy, owing to must take the medicament of more amount chronically, so the morbidity that disease is replaced in the side effect of medicament, antibacterial also produces in reality as clinically problem.And antibiotic use is considered to and might will be expelled in large quantities around the gastric mucosa as the VacA of the cause of disease factor that produces pyloric bacteria along with the destruction of thalline.And antibiotic volume is used and is caused producing danger novel, stronger resistant bacterium in addition.Take all factors into consideration foregoing, now widely used hardly novel 3 doses is ideal Therapeutic Method with therapy also.
In Japan, the infection rate of pyloric bacteria is particularly higher in 40 years old or above a generation, and compares with the America and Europe, and the sickness rate of ulcer disease and gastric cancer is also high, with the Therapeutic Method of resistant bacterium problem, then the value on industry will be very big if found to be free from side effects.
Patent documentation 1: Japanese kokai publication hei 09-002917 communique
Patent documentation 2: Japanese kokai publication hei 09-163969 communique
Patent documentation 3: Japanese kokai publication hei 09-295944 communique
Patent documentation 4: Japanese kokai publication hei 10-025232 communique
Patent documentation 5: TOHKEMY 2000-327582 communique
Patent documentation 6: TOHKEMY 2001-039886 communique
Patent documentation 7: the international openly text that discloses No. 02/07826
Non-patent literature 1:Lancet, 1273-1275 (1983)
Non-patent literature 2:Med.J.Aust., 142,436 (1985)
Non-patent literature 3:Gastroenterology, 102,1575 (1992)
Non-patent literature 4:N.Engl.Med., 328,308 (1993)
Non-patent literature 5:Infect.Immun.63,4154-4160 (1995)
Summary of the invention
Therefore, the object of the present invention is to provide few side effects, the generation that does not have resistant bacterium and prevention, anti-recurrence or treatment chylopoietic disease relevant and medicine, medicine part outer article, the diet product that the VacA that pyloric bacteria produced had neutralization with pyloric bacteria.
The inventor etc. have attempted solving problem by not killing pyloric bacteria but find the VacA that pyloric bacteria is produced not have the factor that poisons in view of these present situations.Poison the factor if found the effective nothing of VacA, then the meaning on medical science, industry is immeasurable.
Lucubrates such as the inventor found that, the polyphenol that exists in Flos lupuli (Flos Humuli Lupuli) and Fructus Mali pumilae a kind of do not have the VacA that pyloric bacteria produced effectively poisons, and then has finished the present invention.This polyphenol contains in the bract part of the immature fruit of Fructus Mali pumilae and Flos lupuli (Flos Humuli Lupuli) especially in large quantities.
This polyphenol that contains in the Flos lupuli (Flos Humuli Lupuli) has following characteristic: promptly be adsorbed in styrene-divinylbenzene resin etc. and polyphenol show affinity resin, by fraction molecular weight (fractionmolecular weight) be 1000 or above ultrafilter membrane do not see through film when handling.In addition, be hydrolyzed generation anthocyanidin when in the alcoholic solution that contains 5% left and right sides hydrochloric acid, heating, be considered to the procyanidin class.In addition, this procyanidin class shows chromatogram shown in Figure 1 in GPC (gel permeation chromatography) analyzes, and shows that in absorbance is analyzed absorbance shown in Figure 2 distributes.
In addition, this polyphenol that contains in Fructus Mali pumilae also is adsorbed in the resin that styrene-divinylbenzene resin etc. and polyphenol show affinity, is hydrolyzed generation anthocyanidin during heating in the alcoholic solution that contains 5% left and right sides hydrochloric acid, is considered to the procyanidin class.
That is, the present invention relates to contain the procyanidin class, be preferably the procyanidin class that comes from Flos lupuli (Flos Humuli Lupuli) or Fructus Mali pumilae VacA nertralizer especially as effective ingredient.
As in and the material of VacA, the Polyphenols that Tombola etc. disclose 5-nitro-2-(3-phenylpropylamine base) benzoic acid, phloretin and a part suppresses to change (Tombola F.et al. by the electric current on the cell membrane that VacA produced, FEBS Lett.543,184-189 (2003)).But also set forth the power on material of rheologyization of inhibition cell membrane in these systems in same document, it doesn't matter for the inhibition of vacuolation and the toxic neutralization of pair cell in the cell that causes with VacA.And, as suppressing the cell membrane disclosed chemical compound of material of rheologyization that powers on,, be not the chemical compound of procyanidin class in these documents though be Polyphenols.
Therefore, come from plant, especially preferably come from the procyanidin class in Flos lupuli (Flos Humuli Lupuli) or the Fructus Mali pumilae and VacA is not had the technology that poisons, up to the present also never reported about use.
Description of drawings
Figure 1 shows that the figure of GPC (gel permeation chromatography) analysis result of the procyanidin class that comes from Flos lupuli (Flos Humuli Lupuli).
Figure 2 shows that the figure of the absorbance distribution of the procyanidin class that comes from Flos lupuli (Flos Humuli Lupuli).
Figure 3 shows that the figure of the HPLC analysis result of the procyanidin class that comes from Flos lupuli (Flos Humuli Lupuli).
Figure 4 shows that the figure that the nothing of the VacA in the gastric carcinoma cells AZ-521 cultured cell poisons.(embodiment 13)
Figure 5 shows that the figure that the nothing of the VacA in the human renal carcinoma cell G401 cultured cell poisons.(embodiment 13)
Figure 6 shows that the VacA that suppresses in the gastric carcinoma cells AZ-521 cultured cell enters the figure of cell.(embodiment 14)
Figure 7 shows that the VacA that suppresses in the human renal carcinoma cell G401 cultured cell enters the figure of cell.(embodiment 14)
The specific embodiment
As the raw material of VacA nertralizer of the present invention, except the immature fruit of Fructus Mali pumilae, go back the climing and bract part of preferably beer flower, particularly can be not the each several part of Fructus Mali pumilae or Flos lupuli (Flos Humuli Lupuli) not be separated and whole the use yet.
So-called Flos lupuli (Flos Humuli Lupuli) bract is meant the material of removing the lupulin part and obtain from the cone of Flos lupuli (Flos Humuli Lupuli), in general, after the hop cone pulverizing, by screening lupulin is partly removed, thereby is obtained the Flos lupuli (Flos Humuli Lupuli) bract.But, in nearest brewing,, following tendency is arranged: promptly will not remove to the useless Flos lupuli (Flos Humuli Lupuli) bract of brewing in order to save the trouble that the screening of Flos lupuli (Flos Humuli Lupuli) bract is removed, but be graininess, and be used for brewing as hop pellet with the hop cone direct forming.Therefore, as raw material of the present invention, as long as contain the climing and bract of Flos lupuli (Flos Humuli Lupuli), there is no particular limitation, though will contain the hop cone of Flos lupuli (Flos Humuli Lupuli) bract or hop pellet as raw material also without any problem.
As the manufacture method that from Flos lupuli (Flos Humuli Lupuli), obtains the VacA nertralizer be, Flos lupuli (Flos Humuli Lupuli) is climing, bract or the material that contains hop cone, the hop pellet of Flos lupuli (Flos Humuli Lupuli) bract or contain these Flos lupuli (Flos Humuli Lupuli) plants parts be as raw material, and the aqueous solution with the blended organic solvent of water such as its water or 80v/v% or following alcohol, acetone, acetonitrile is extracted.As preference, can enumerate ethanol is 50v/v% or following aquiferous ethanol.Raw material is preferably about 1:20~100 (weight ratio) with the ratio of extracting solvent, extract preferably 4~95 ℃, carry out about 20~60 minutes under stirring.Obtain extracting solution by filtration, also can use filtration auxiliary material such as perlite this moment if desired.
Solvent is removed from the extracting solution that obtains like this by usual ways such as concentrated, lyophilization, spray dryinges, can be obtained VacA nertralizer as pulverulence.Here the VacA nertralizer that obtains is enough to supply in practicality, but if desired, also can further improve its purity by the method for following use adsorbent resin.But this process is the operation that is used to improve the purity of VacA nertralizer eventually, and unwanted words also can be omitted.
Will with the synthetic resin that Polyphenols has an affinity make granular after, handle said extracted liquid, concentrate the VacA nertralizer.This operation can be passed through the Flos lupuli (Flos Humuli Lupuli) extracting solution in being filled with the post of granular synthetic resin, behind the thorough washing post, with the VacA nertralizer stripping that is adsorbed on the post; Also granular resin can be immersed in the Flos lupuli (Flos Humuli Lupuli) extracting solution, be carried out to batch processing.
When making the VacA nertralizer be adsorbed in synthetic resin, the Flos lupuli (Flos Humuli Lupuli) extracting solution is cooled to about 15~30 ℃ room temperature after, if desired,, preferably in advance the organic solvent concentration of extracting solution is reduced by concentrating under reduced pressure etc. in order to improve adsorption efficiency.As the material of synthetic adsorbent, also can use hydroxypropylation glucosan, hydrophilic ethylene polymer, styrene-divinyl benzene polymers etc.
Next wash synthetic resin, can further improve the purity of VacA nertralizer.The ethanol water that preferably makes water or 1~10w/w% preferably uses the quantity of solvent of about 1~10 times of amount of resin to wash as the solvent that is used to wash.
Then, the VacA nertralizer is broken away from stripping from the synthetic resin that is adsorbed with Polyphenols.As the solvent that uses in the stripping, can use aqueous alcohol, aqueous acetone, contain water-acetonitrile etc., as more preferred example, can enumerate 30w/w% or above ethanol water or ethanol.The amount of passing through in resin of stripping solvent is preferably about 2~6 times of amount of resin.
By concentrate, usual ways such as lyophilization, spray drying remove from the gained dissolution fluid and desolvate, and can obtain the VacA nertralizer as pulverulence.In addition, also alcohol, acetone, acetonitrile etc. can be reclaimed and utilize again during concentrating under reduced pressure.Employed synthetic resin can use after washing with 80v/v% or above alcohol-water solution, the sodium hydrate aqueous solution about 0.05N etc. repeatedly.
The VacA nertralizer that obtains like this can also can further improve its purity by the method for using following ultrafilter membrane directly in practical application.But this process is the operation that is used to improve the purity of VacA nertralizer eventually, and unwanted words also can be omitted.
With the VacA nertralizer that utilizes said method to obtain be dissolved in water or with the blended organic solvent of water in, with the fraction molecular weight be 1000 or above ultrafilter membrane handle.As the material of film,, can be not particularly limited to use so long as common materials as the ultrafilter membrane material such as cellulose, cellulose acetate, polysulfones, polypropylene, polyester, polyether sulfone, PVDF get final product.In addition, the fraction molecular weight if 1000 or more than, then there is not special problem all can use, if but use the excessive film of fraction molecular weight, then output sharply descends, and when using the little film of fraction molecular weight, and it is elongated then to handle the needed time, therefore priority fractionated molecule amount is about 5000~50,000 ultrafilter membrane.In addition, handle also according to ratio different and different of extracting solvent types, extracting solvent and Flos lupuli (Flos Humuli Lupuli) or Flos lupuli (Flos Humuli Lupuli) bract, but preferred process to the quantitative change of general top debris about 1/10~1/100 when beginning for handling.The pressure of this moment is also according to the difference of ultrafilter membrane, defecator and difference, but preferably probably is 0.1~10.0kg/cm
2In addition, if desired, also appropriate solvent such as water will be handled once top debris dilution once more, and carry out same processing again, thereby improve purity.
By concentrate, usual ways such as lyophilization, spray drying remove the solvent in the debris of gained top, can obtain the VacA nertralizer as pulverulence.In addition, also alcohol, acetone, acetonitrile etc. can be reclaimed and utilize again during concentrating under reduced pressure.
The VacA nertralizer that obtains like this is yellowish pink, brown or the flaxen powder of slightly bitter odorless, be adsorbed in polyphenol have affinity synthetic resin and by the fraction molecular weight be 1000 or above ultrafilter membrane do not see through the procyanidin of film when handling.
Yield is 0.5~20.0w/w% when converting with Flos lupuli (Flos Humuli Lupuli) bract weight, is 0.5~15.0w/w% when converting with hop cone weight.
As the manufacture method that from Fructus Mali pumilae, obtains the VacA nertralizer, can be with the Fructus Mali pumilae fruit, be preferably the immature fruit of Fructus Mali pumilae, squeeze the juice by squeezing, make the solution that contains the VacA nertralizer, this solution is made powder by usual ways such as concentrated, lyophilization, spray dryinges use.In addition, also can be as required, use to be filled with the post etc. that polyphenol is had the granular resin etc. of affinity, the VacA nertralizer is refining, use after improving purity.It is identical that this operation and the VacA nertralizer that will obtain from Flos lupuli (Flos Humuli Lupuli) concentrate purified operation.
The VacA nertralizer that obtains like this can be made preparation with normally used carrier, adjuvant, additive etc., can be according to conventional method as oral, non-oral products, medicine and use, can also with make the diet product after food material mixes.
Medicine has tablet, capsule, granule, syrup etc. as oral agents, and external agent such as ointment, Emulsion, water preparation are arranged as non-oral agents, injections such as sterile solution agent, suspensoid etc.These goods are thrown when giving to human body as medicine, given 2mg~500mg, promptly throw with the whole day amount of 2mg~1000mg and give, can fully reach its effect with every day 1~several throwing.
The medicine that contains VacA nertralizer of the present invention can be desired unit volume form with the last remedium constituens that allows of physiology, carrier, excipient, blender, stabilizing agent, flavouring agent etc.The adjuvant drug that is mixed in tablet, capsule is following material: i.e. bonding agent such as tragacanth, arabic gum, corn starch, gelatin, excipient such as microcrystalline Cellulose, swelling agents such as corn starch, full gelling starches, alginic acid, lubricants such as magnesium stearate, sweeting agents such as sucrose, lactose, glucide, flavouring agents such as Herba Menthae, acamono oil, Fructus Pruni pseudocerasi.In addition, during for capsule, in above-mentioned material, can also further contain liquid-carriers such as oils and fats, and other materials can be used as coverture or with additive method the physical aspect of preparation is changed.For example, tablet can be covered by Lac, Saccharum Sinensis Roxb..Syrup or elixir can contain sucrose as sweeting agent, as the methyl parahydroxybenzoate or the flavouring agents such as propyl p-hydroxybenzoate, pigment and Fructus Pruni pseudocerasi or orange perfume (or spice) of antiseptic.
The aseptic composite that is used for injection can be filled a prescription by following common method: the shape material alive that makes remedium constituenses such as water for injection, Oleum sesami, Oleum Cocois, Oleum Arachidis hypogaeae semen, the natural product vegetable oil of Semen Gossypii wet goods, the perhaps method of dissolving of synthctic fat remedium constituens such as ethyl oleate or suspendible.In addition, can also cooperate buffer agent, antiseptic, antioxidant etc. as required.As the external agent, can use vaseline as base material, paraffin, oils, lanoline, Polyethylene Glycol etc., make ointment, Emulsion etc. by method commonly used.
The diet product that contain VacA nertralizer of the present invention can be the forms of above-mentioned preparation, also can add in raw-food material separately and will measure with forms such as sugar, crispbread, cooky, beverages, and carry out processing and manufacturing by manufacture method commonly used.As the picked-up of health food, functional food, owing to be to be used for prevent disease and to keep health, make therefore that to divide orally ingestible for several times every day, comprise full-time amount be that the processed goods of 5mg~500mg absorbs.
When in these diet product, adding the VacA nertralizer, the VacA nertralizer directly can be added with pulverulence, but preferably the VacA nertralizer is made 1~2% aqueous solution, the solution or the alcoholic solution of alcohol-water solution, become 1~10 according to ultimate density, 000ppm, the mode that is preferably 100~5000ppm are added in the diet product.
VacA nertralizer of the present invention is being that purpose can be used as preventive when using to prevent this chylopoietic disease, in the recurrence with this chylopoietic disease of once curing of prevention is that purpose can be used as anti-recurrence agent when using, so that to treat this chylopoietic disease be that purpose can be used as bacteria remover when using by removing pyloric bacteria.In addition,, can use eradicating agent for helicobacter pylori of the present invention separately, also can be used in combination with proton pump inhibitor and/or antibiotic in prevention, when preventing recurrence or treating this chylopoietic disease.
Dosage on the one of VacA nertralizer of the present invention can wait according to other conditions, disease degrees such as its usage, patient's age, sexes and suitably select, usually the amount as the The compounds of this invention of effective ingredient is about per day for adults 0.1~2000mg, is preferably about 0.5~1800mg, is preferably especially about 1.0~1500mg, divide 1~4 administration every day, as can be in administration on an empty stomach.
Below enumerate embodiment, but the present invention is not limited by it.
(preparing the VacA nertralizer from hop cone) by the gel-type synthetic adsorbent
In mortar, the 20g hop cone is pulverized,, extracted 40 minutes down at 95 ℃ with the water stirring of 2L.Put coldly after the filtration, by being filled with the post of 80ml hydrophilic ethylene fluoropolymer resin, then use 5% ethanol water of 400ml to wash extracting solution.Then, by 400ml 80% ethanol water, reclaim identical dissolution fluid in same post, lyophilization obtains the VacA nertralizer of 800mg as the slightly bitter pale yellow powder state of odorless.The yield that obtains from Flos lupuli (Flos Humuli Lupuli) is 4%.
(preparing the VacA nertralizer from the Flos lupuli (Flos Humuli Lupuli) bract) by the gel-type synthetic adsorbent
Stir 20g Flos lupuli (Flos Humuli Lupuli) bract with 600ml 50% ethanol water, extracted 20 minutes down at 30 ℃.Filter the back concentrating under reduced pressure, by being filled with the post of 80ml styrene-divinylbenzene resin, then the water with 400ml washs with this concentrated solution.Then, by the 400ml80% ethanol water, reclaim identical dissolution fluid in same post, lyophilization obtains the VacA nertralizer of 1.6g as the slightly bitter pale yellow powder state of odorless.The yield that obtains from the Flos lupuli (Flos Humuli Lupuli) bract is 8%.
Embodiment 3
(preparing the VacA nertralizer from hop cone) by ultrafilter membrane
In mortar, the 20g hop cone is pulverized,, extracted 40 minutes down at 95 ℃ with the water stirring of 2L.Put coldly after the filtration, to utilize the fraction molecular weight be 50,000 ultrafilter membrane, at 1.0kg/cm
2, handle extracting solution under the room temperature, until becoming 20ml.With the top debris drying under reduced pressure of gained, obtain the VacA nertralizer of 200mg as the slightly bitter pale yellow powder state of odorless.The yield that obtains from Flos lupuli (Flos Humuli Lupuli) is 1%.
Embodiment 4
(preparing the VacA nertralizer from the Flos lupuli (Flos Humuli Lupuli) bract) by ultrafilter membrane
Stir 20g Flos lupuli (Flos Humuli Lupuli) bract with 600ml 50% ethanol water, extracted 40 minutes down at 80 ℃.After the filtration, to utilize the fraction molecular weight be 1,000 ultrafilter membrane, at 3.0kg/cm
2, handle extracting solution under the room temperature, until becoming 60ml.With the top debris lyophilization of gained, obtain the VacA nertralizer of 0.8g as the slightly bitter pale yellow powder state of odorless.The yield that obtains from the Flos lupuli (Flos Humuli Lupuli) bract is 4%.
Embodiment 5
(the further refining and qualitative analysis of VacA nertralizer)
0.8g embodiment 2 resulting VacA nertralizers are dissolved in 500ml 10% ethanol water, and to utilize the fraction molecular weight be 5,000 ultrafilter membrane, at 1.0kg/cm
2, handle under the room temperature, until becoming 20ml.With the top debris lyophilization of gained, obtain the VacA nertralizer of 0.4g as the slightly bitter yellowish pink pulverulence of odorless.When under the following conditions this powder being carried out the HPLC analysis, show characteristic chromatogram shown in Figure 3, in addition, the catechuic acid that carries out one of the Polyphenols quantitative method as common is quantitatively when (food standard analytic process), be scaled catechuic acid content, the value that obtains is 40.6%.
(HPLC condition) device: Tianjin, island LC-10A system, chromatographic column: ODS-80TM (Toso, 4.6mmI.D. * 25cm), mobile phase: from (A liquid: B liquid)=(100: 0) to 30 minutes straight line gradient, the A liquid of (50: 50): 5% acetonitrile (containing 0.1%HCl), B liquid: acetonitrile, sample size: 20 μ g, detect: the multi-wavelength of 200~300nm detects.
Embodiment 6
(preparing the VacA nertralizer) from the immature fruit of Fructus Mali pumilae
With the immature fruit (average weight is 5.03g) of 400g Fructus Mali pumilae after 1% hydrochloric acid acidic methanol homogenizes, (3 times) are extracted on reflux limit, limit, the extracting solution concentrating under reduced pressure is heated up in a steamer nor-alcohol after, add chloroform and carry out layering (2 times), reclaim water layer, filter the back adding distil water to 200ml.Then, make with extra care by the solid phase extraction that has used Sep-pak C18, lyophilization obtains the VacA nertralizer.
Embodiment 7
(tablet, capsule)
According to embodiment 5 resulting material 10.0g
Lactose 75.0g
Magnesium stearate 15.0g
Add up to 100.0g
With above-mentioned each weight portion uniform mixing, make tablet, capsule according to well-established law.In addition, replace adding 1,2,3,4,6 resulting materials respectively, obtain tablet, capsule similarly according to embodiment according to embodiment 5 resulting materials.
Embodiment 8
(powder, granule)
According to embodiment 5 resulting material 20.0g
Starch 30.0g
Lactose 50.0g
Add up to 100.0g
With above-mentioned each weight portion uniform mixing, make powder, granule according to well-established law.In addition, replace adding 1,2,3,4,6 resulting materials respectively, obtain powder, granule similarly according to embodiment according to embodiment 5 resulting materials.
Embodiment 9
(injection)
According to embodiment 5 resulting material 1.0g
Surfactant 9.0g
Normal saline 90.0g
Add up to 100.0g
Above-mentioned each weight portion heating is mixed, sterilizes, make injection.In addition, replace adding 1,2,3,4,6 resulting materials respectively, obtain injection similarly according to embodiment according to embodiment 5 resulting materials.
(sugar)
Sucrose 20.0g
Maltose syrup (75% solid constituent) 70.0g
Water 9.5g
Coloring agent 0.45g
Spice 0.045g
According to embodiment 5 resulting material 0.005g
Add up to 100.0g
Use each composition of above-mentioned each weight portion, make sugar according to well-established law.In addition, replace adding 1,2,3,4,6 resulting materials respectively, obtain sugar similarly according to embodiment according to embodiment 5 resulting materials.
Embodiment 11
(fruit juice)
Concentrate Fructus Citri tangerinae fruit juice 15.0g
Fructose 5.0g
Citric acid 0.2g
Spice 0.1g
Pigment 0.15g
Sodium ascorbate 0.048g
According to embodiment 5 resulting material 0.002g
Water 79.5g
Add up to 100.0g
Use each composition of above-mentioned each weight portion, make fruit juice according to well-established law.In addition, replace adding 1,2,3,4,6 resulting materials respectively, obtain fruit juice similarly according to embodiment according to embodiment 5 resulting materials.
Embodiment 12
(cooky)
Soft flour 32.0g
Whole egg 16.0g
Butter 16.0g
Saccharum Sinensis Roxb. 25.0g
Water 10.8g
Yeast powder 0.198g
According to embodiment 5 resulting material 0.002g
Add up to 100.0g
Use each composition of above-mentioned each weight portion, make cooky according to well-established law.In addition, replace adding 1,2,3,4,6 resulting materials respectively, obtain cooky similarly according to embodiment according to embodiment 5 resulting materials.
Embodiment 13
VacA is to the cell toxicity test of cultured cell
The cell strain G401 cell that will come from the cell strain AZ-521 cell of people's gastric cancer or come from people's renal carcinoma is adjusted into 2.0 * 10
5The suspension of cell/ml.After being sub-packed in its 100 μ l in 96 orifice plates, place an evening, prepare the monofilm of each cell.Certain density VacA is mixed with the embodiment 5 or the 6 resulting VacA nertralizers of various concentration, cultivated 30 minutes down, afterwards it is added in the above-mentioned plate at 37 ℃.The ultimate density of VacA is 120nM, and embodiment 5 or 6 ultimate density are 0~100 μ g/ml.With plate at 5%CO
2In the atmosphere, 37 ℃ cultivate down after 8 hours, the degree (Ab540) that enters to cavity by dimethyl diaminophenazine chloride (0.05%PBS solution) is estimated the toxicity of VacA pair cell.It the results are shown in Fig. 4 and Fig. 5.Depend on the concentration of embodiment 5 and 6 resulting VacA nertralizers,, all poisoned by nothing by the cytotoxicity that VacA caused with respect to AZ-521 cell and G401 cell.
Embodiment 14
Combination to cultured cell
The cell strain G401 cell that will come from the cell strain AZ-521 cell of people's gastric cancer or come from people's renal carcinoma is adjusted into 2.0 * 10
5The suspension of cell/ml.After being sub-packed in its 100 μ 1 in 96 orifice plates, place an evening, prepare the monofilm of each cell.With the biotin labeled VacA of various concentration and certain density embodiment 5 or 6 resulting VacA nertralizers 37 ℃ cultivate 30 minutes down after, be added in the monofilm of cell.The ultimate density of VacA is 0~100nM, and embodiment 5 or 6 ultimate density are 10 μ g/ml.With the monofilm of cell at 5%CO
2, cultivate after 4 hours in 37 ℃ the incubator, with 0.25% glutaraldehyde with cell fixation.Utilize the colour developing (Ab450nm) of the horseradish peroxidase (Pharmacia) of avidin 9 white marker and TMBZ pigment to estimate the amount of the biotin labeled VacA that adheres to cell surface.It the results are shown in Fig. 6 and Fig. 7.Depend on the concentration of embodiment 5 or 6 resulting VacA nertralizers, the combination of VacA pair cell is suppressed.
Embodiment 15
Mice stomach injury experiment
To gone on a hunger strike 24 hours (only freely absorbing drinking-water) 4 age in week the C57BL/6J mice, use the device (ingestion probe) of ingesting to throw to give VacA that to be equivalent to every 10g body weight be 5 μ g and the embodiment 5 resulting materials of 50~250 μ g.Separate letting animals feed, cage of a mice.After the administration 48 hours, stomach is extractd.To extract specimen 10% formalin fixed, with its front and back of stereoscopic microscope observing.Fixed preparation is carried out hematoxylin have a liking for red colouring,,, estimate the counting of degree of gastric injury according to people's such as Ghiara method (Ghiara.P., et al.Infect.Immun.63,4154-4160. (1995)).It the results are shown in table 1.Embodiment 5 has suppressed the damage of stomach significantly.
Table 1
Sequence number | Sample | Gastric injury is counted |
1 | Phosphate buffer | 1.6±0.8 |
2 | Embodiment 5 (250 μ g) | 1.8±0.8 |
3 | VacA (5 μ g) | 3.0±0.8 |
4 | VacA (5 μ g)+embodiment 5 (50 μ g) | 2.4±1.0 |
5 | VacA (5 μ g)+embodiment 5 (100 μ g) | 2.2±0.8 * |
6 | VacA (5 μ g)+embodiment 5 (250 μ g) | 2.2±0.8 * |
*Expression is compared with 3, and risk is that there were significant differences below 5%.
In sum, VacA nertralizer of the present invention is owing to have VacA is not had the effect that poisons, therefore with the VacA be in the prevention of infection disease of pathogenic factor and the treatment effectively.It is that the preventing/treating agent and the experiment on the biochemistry of infection disease of pathogenic factor carried out commercialization with reagent etc. that the present invention's product can be used as with the VacA.
As the chylopoietic disease relevant, can gastric ulcer, duodenal ulcer, gastritis, gastric cancer, MALT lymphoma etc. be shown example with pyloric bacteria.
Claims (15)
1, a kind of procyanidin class with VacA neutralization (nothing poisons) effect that helicobacter pylori is produced.
2, procyanidin class as claimed in claim 1, this procyanidin class comes from Flos lupuli (Flos Humuli Lupuli) or Flos lupuli (Flos Humuli Lupuli) bract.
3, procyanidin class as claimed in claim 1, this procyanidin class comes from Fructus Mali pumilae.
4, the chylopoietic disease's relevant with helicobacter pylori preventive, anti-recurrence agent or therapeutic agent, it contains the described procyanidin class of claim 1 as effective ingredient.
5, the chylopoietic disease's relevant with helicobacter pylori preventive, anti-recurrence agent or therapeutic agent, it contains the described procyanidin class of claim 2 as effective ingredient.
6, the chylopoietic disease's relevant with helicobacter pylori preventive, anti-recurrence agent or therapeutic agent, it contains the described procyanidin class of claim 3 as effective ingredient.
7, the nertralizer of the VacA that helicobacter pylori produced, it contains the described procyanidin class of claim 1 as effective ingredient.
8, the nertralizer of the VacA that helicobacter pylori produced, it contains the described procyanidin class of claim 2 as effective ingredient.
9, the nertralizer of the VacA that helicobacter pylori produced, it contains the described procyanidin class of claim 3 as effective ingredient.
10, contain the medicine part outer article of the described procyanidin class of claim 1 as effective ingredient.
11, contain the medicine part outer article of the described procyanidin class of claim 2 as effective ingredient.
12, contain the medicine part outer article of the described procyanidin class of claim 3 as effective ingredient.
13, contain the diet product of the described procyanidin class of claim 1 as effective ingredient.
14, contain the diet product of the described procyanidin class of claim 2 as effective ingredient.
15, contain the diet product of the described procyanidin class of claim 3 as effective ingredient.
Applications Claiming Priority (3)
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JP2003344433 | 2003-10-02 | ||
JP344433/2003 | 2003-10-02 | ||
PCT/JP2004/014979 WO2005032542A1 (en) | 2003-10-02 | 2004-10-04 | Neutralizing agent for cavitating toxin |
Publications (2)
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CN1863524A true CN1863524A (en) | 2006-11-15 |
CN1863524B CN1863524B (en) | 2010-10-06 |
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US (2) | US20070009619A1 (en) |
JP (1) | JPWO2005032542A1 (en) |
KR (1) | KR100803375B1 (en) |
CN (1) | CN1863524B (en) |
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JPWO2006115123A1 (en) * | 2005-04-19 | 2008-12-18 | アサヒビール株式会社 | Virus inactivating agent |
JP4746391B2 (en) * | 2005-09-21 | 2011-08-10 | アサヒビール株式会社 | Method for designing functionality and / or taste of food and drink, and food and drink |
ATE523202T1 (en) * | 2006-11-13 | 2011-09-15 | Nookandeh Baumgaertner Aslieh Dr | EXTRACTION PROCESS FOR THE CLASSIFIED EXTRACTION AND SEPARATION OF PLANT INGREDIENTS AND THEIR USE |
JP5685280B2 (en) | 2013-03-28 | 2015-03-18 | サントリーホールディングス株式会社 | Method for producing beer-taste beverage using hop lees |
CN103570664B (en) * | 2013-11-13 | 2015-07-01 | 长沙蓝威生物制品有限公司 | Method of extracting procyanidine from huckleberries |
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GB8518289D0 (en) * | 1985-07-19 | 1985-08-29 | Inverni Della Beffa Spa | Obtaining proanthocyanidine a2 |
JPH09221484A (en) * | 1996-02-14 | 1997-08-26 | Kikkoman Corp | Production of proanthocyanidin |
CA2250792C (en) * | 1996-04-02 | 2011-09-13 | Mars, Incorporated | Cocoa extract compounds and methods for making and using the same |
JPH1025247A (en) * | 1996-07-10 | 1998-01-27 | Asahi Breweries Ltd | Preventive and therapeutic agent for gastritis and gastric and duodenal ulcer |
JPH10218769A (en) * | 1997-02-06 | 1998-08-18 | Kikkoman Corp | Antiulcer agent |
US5972985A (en) * | 1997-11-03 | 1999-10-26 | Cytos Pharmaceuticals, Llc | Histidine containing nutriceutical compositions |
JPH11180888A (en) * | 1997-12-24 | 1999-07-06 | Otsuka Pharmaceut Co Ltd | Antimicrobial, infection preventive and food product against helicobacter pylori bacteria |
JP2000159669A (en) * | 1998-11-26 | 2000-06-13 | Mikoo:Kk | Urease inhibitor, medicine and food composition containing the inhibitor and measurement of urease activity |
WO2002078726A1 (en) * | 2001-03-28 | 2002-10-10 | Asahi Breweries,Ltd. | Proteotoxin neutralizer |
JP2003026587A (en) * | 2001-07-11 | 2003-01-29 | Nobuo Yamaguchi | Bacterial removing agent for helicobacter pylori |
US20030161841A1 (en) * | 2002-02-01 | 2003-08-28 | Kazuo Sakuma | Preventive and therapeutic agents for microbe-related syndromes including HIV |
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2004
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- 2004-10-04 JP JP2005514515A patent/JPWO2005032542A1/en active Pending
- 2004-10-04 CN CN2004800288070A patent/CN1863524B/en not_active Expired - Fee Related
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US20080275109A1 (en) | 2008-11-06 |
JPWO2005032542A1 (en) | 2007-11-15 |
US20070009619A1 (en) | 2007-01-11 |
KR20060058729A (en) | 2006-05-30 |
CN1863524B (en) | 2010-10-06 |
WO2005032542A1 (en) | 2005-04-14 |
TWI279231B (en) | 2007-04-21 |
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